Extracellular Vesicles (EVs) have received considerable attention in recent years, both as mediators of intercellular communication pathways that lead to tumor progression, and as potential sources for discovery of novel cancer biomarkers. For many years, research on EVs has mainly investigated either the mechanism of biogenesis and cargo selection and incorporation, or the methods of EV isolation from available body fluids for biomarker discovery. Recent studies have highlighted the existence of different populations of cancer-derived EVs, with distinct molecular cargo, thus pointing to the possibility that the various EV populations might play diverse roles in cancer and that this does not happen randomly. However, data attributing cancer specific intercellular functions to given populations of EVs are still limited. A deeper functional, biochemical and molecular characterization of the various EV classes might identify more selective clinical markers, and significantly advance our knowledge of the pathogenesis and disease progression of many cancer types.
Treatment of prostate cancer (PC) by androgen suppression promotes the emergence of aggressive variants that are androgen receptor- (AR-) independent. Here we identify the transcription factor ONECUT2 (OC2) as a master regulator of AR networks in metastatic castration-resistant prostate cancer (mCRPC). OC2 acts as a survival factor in mCRPC models, suppresses the AR transcriptional program by direct regulation of AR target genes and the AR licensing factor FOXA1, and activates genes associated with neural differentiation and progression to lethal disease. OC2 appears active in a substantial subset of human prostate adenocarcinoma and neuroendocrine tumors. Inhibition of OC2 by a newly identified small molecule suppresses metastasis in mice. These findings suggest that OC2 displaces AR-dependent growth and survival mechanisms in many cases where AR remains expressed, but where its activity is bypassed. OC2 is also a potential drug target in the metastatic phase of aggressive PC.
Prostate cancer cells release atypically large extracellular vesicles (EVs), termed large oncosomes, which may play a role in the tumor microenvironment by transporting bioactive molecules across tissue spaces and through the blood stream. In this study, we applied a novel method for selective isolation of large oncosomes applicable to human platelet-poor plasma, where the presence of caveolin-1-positive large oncosomes identified patients with metastatic disease. This procedure was also used to validate results of a miRNA array performed on heterogeneous populations of EVs isolated from tumorigenic RWPE-2 prostate cells and from isogenic non-tumorigenic RWPE-1 cells. The results showed that distinct classes of miRNAs are expressed at higher levels in EVs derived from the tumorigenic cells in comparison to their non-tumorigenic counterpart. Large oncosomes enhanced migration of cancer-associated fibroblasts (CAFs), an effect that was increased by miR-1227, a miRNA abundant in large oncosomes produced by RWPE-2 cells. Our findings suggest that large oncosomes in the circulation report metastatic disease in patients with prostate cancer, and that this class of EV harbors functional molecules that may play a role in conditioning the tumor microenvironment.
Rifaximin is more effective than other antibiotics in the treatment and retreatment of IBS.
Adult spinal deformity (ASD) is characterized by three-dimensional abnormalities of the thoracic or thoracolumbar spine that exerts significant impacts on the health-related quality of life (HRQoL). With the important effects that deformity of the sagittal plane exerts on the HRQoL, there have been paradigm shifts in ASD evaluation and management. Loss of lumbar lordosis is recognized as a key driver of ASD followed by reducing kyphosis, pelvic retroversion, and knee flexion. The Scoliosis Research Society (SRS)-Schwab classification reflects the sagittal spinopelvic parameters that correlate pain and disability in ASD patients. Although the SRS-Schwab classification provides a realignment target framework for surgeons, a structured patient-specific systemic approach is crucial for the process of decision-making. ASD management should be focused on restoring age-specific harmonious alignment and should consider the comorbidities and risk factors of each patient to prevent catastrophic complications and enhance the HRQoL.
A light-controlled reversible binding switch based on photochromic 3H-naphtho [2,1-b]pyran is under development for studying cellular oscillatory calcium signals. The binding affinities of the closed and open forms of substituted naphthopyran 1 for Ca 2+ , Mg 2+ , and Sr 2+ in buffer were determined. The photochemically ring-opened form of the receptor exhibited increased affinity compared to the thermally stable closed form of the receptor. The binding affinity difference for Ca 2+ was ∼77-fold at pH 7.6. Calcium (Ca 2+ ) is a second messenger in many cell types, where it is used to translate extracellular signals into a wide variety of intracellular events. 1 Important cellular processes are controlled by Ca 2+ , and many disease states are associated with defects in the calcium signalosome. Manipulation of Ca 2+ concentration in cells through cage compounds is an important tool for learning about this widespread signaling system. 2 Caged Ca 2+ compounds undergo irreversible photochemical reactions that either release or take up Ca 2+ when triggered. However, cage compounds are less well suited to the examination of oscillatory calcium signals, which may encode information through both amplitude and frequency modulation. The origin of these oscillatory signals is known, but their effects at a molecular level are less well understood. There is a need to develop new methodologies to study the effects of spatiotemporal changes in Ca 2+ concentration. In the present work, we report the synthesis and characterization of compound 1, a new watersoluble 3H-naphtho[2,1-b]pyran with an iminodiacetic acid substituent at position 5 ( Figure 1). This compound is designed so that the open form of 1 will exhibit a higher affinity for Ca 2+ than the closed form. The binding affinities of closed and open forms of compound 1 were determined, and the effects of buffer composition and pH, on this reversible calcium binding photoswitch were also examined.Naphthopyran chelator 1 was obtained in five steps (Scheme 1 and Supporting Information) with an overall yield of 11%. Compound 1 is soluble up to ∼5.7 × 10 -4 M in aqueous solutions buffered at pH 8.7.Complexation of the closed form of 1 with metal ions was examined spectroscopically. The UV-vis spectra of 1 show minimal changes upon addition of excess Mg 2+ , Ca 2+ , and Sr 2+ ( Figure S1, Supporting Information). The addition of metal ions to the closed form of 1 did not result in any detectable thermal ring opening induced by metal complexation, unlike that observed for some photochromic chelators. 5d,7d,8 Small but significant and reproducible 1 H NMR shifts were observed upon addition of metal ions (Table S2, Supporting Information). One or more aromatic protons moved downfield upon addition of all metals to the closed form of 1. The methylene protons only shifted when calcium was added, and they moved upfield. The same pattern of complexation-induced shifting, but with smaller magnitudes, was also observed upon the addition of the same three metals to phenyliminodi...
Significant relations were found between correction rate of middle, and distal curvature, and postoperative shoulder balance. In addition, preoperative shoulder level difference can be a determinant of postoperative shoulder balance.
Introduction: Intervertebral disc (IVD) degeneration is often associated with low back pain and radiating leg pain. The purpose of this study is to develop a reproducible and standardized preclinical model of painful lumbar IVD degeneration by evaluation of structural and behavioral changes in response to IVD injury with increasing needle sizes. This model can be used to develop new therapies for IVD degeneration.Methods: Forty-five female Sprague Dawley rats underwent anterior lumbar disc needle puncture at levels L4-5 and L5-6 under fluoroscopic guidance. Animals were randomly assigned to four different experimental groups: needle sizes of 18 Gauge (G), 21G, 23G, and sham control. To monitor the progression of IVD degeneration and pain, the following methods were employed: μMRI, qRT-PCR, histology, and biobehavioral analysis.Results: T1-and T2-weighted μMRI analysis showed a correlation between the degree of IVD degeneration and needle diameter, with the most severe degeneration in the 18G group. mRNA expression of markers for IVD degeneration markers were dysregulated in the 18G and 21G groups, while pro-nociceptive markers were increased in the 18G group only. Hematoxylin and Eosin (H&E) and Alcian Blue/ Picrosirius Red staining confirmed the most pronounced IVD degeneration in the 18G group. Randall-Selitto and von Frey tests showed increased hindpaw sensitivity in the 18G group. Conclusion:Our findings demonstrate that anterior disc injury with an 18G needle creates severe IVD degeneration and mechanical hypersensitivity, while the 21G needle results in moderate degeneration with no increased pain sensitivity. Therefore, needle sizes should be selected depending on the desired phenotype for the pre-clinical model.
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